Department of Chemical and Biomolecular Engineering, University of California at Berkeley Berkeley, CA, USA.
Front Microbiol. 2011 Oct 4;2:204. doi: 10.3389/fmicb.2011.00204. eCollection 2011.
Vectors based on adeno-associated viruses (AAV) have shown considerable promise in both preclinical models and increasingly in clinical trials. However, one formidable challenge is pre-existing immunity due to widespread exposure to numerous AAV variants and serotypes within the human population, which affect efficacy of clinical trials due to the accompanying high levels of anti-capsid neutralizing antibodies. Transient immunosuppression has promise in mitigating cellular and humoral responses induced by vector application in naïve hosts, but cannot overcome the problem that pre-existing neutralizing antibodies pose toward the goal of safe and efficient gene delivery. Shielding of AAV from antibodies, however, may be possible by covalent attachment of polymers to the viral capsid or by encapsulation of vectors inside biomaterials. In addition, there has been considerable progress in using rational mutagenesis, combinatorial libraries, and directed evolution approaches to engineer capsid variants that are not recognized by anti-AAV antibodies generally present in the human population. While additional progress must be made, such strategies, alone or in combination with immunosuppression to avoid de novo induction of antibodies, have strong potential to significantly enhance the clinical efficacy of AAV vectors.
基于腺相关病毒（AAV）的载体在临床前模型和越来越多的临床试验中都显示出了很大的潜力。然而，一个巨大的挑战是由于人类群体中广泛接触到多种 AAV 变体和血清型而导致的预先存在的免疫。由于伴随的高水平抗衣壳中和抗体，这会影响临床试验的效果。短暂的免疫抑制有望减轻载体在幼稚宿主中应用引起的细胞和体液反应，但不能克服预先存在的中和抗体对安全有效的基因传递目标所构成的问题。通过共价连接聚合物到病毒衣壳上或通过将载体封装在生物材料内，AAV 可以免受抗体的影响。此外，通过合理的诱变、组合文库和定向进化方法来工程化衣壳变体，使其不被通常存在于人群中的抗 AAV 抗体识别，已经取得了相当大的进展。虽然还需要进一步的进展，但这些策略，单独或与免疫抑制联合使用以避免新诱导的抗体，具有显著增强 AAV 载体的临床疗效的强大潜力。
